Packaging made of plastics frequently protect pharmaceutical solutions such as dialysis solutions from changes of their composition for example by outgassing of solution components on the one hand and from outside factors like humidity or oxygen on the other hand. Thus plastic packing materials improve the shelf life and stability of these products during storage. Furthermore plastic packaging has for example the advantage of a lower weight and an easier handling compared to glass bottles. In addition their properties such as stability, elasticity or permeability to gases can be matched to particular requirements within a wide range of possibilities. On the other hand plastics harbor the risk that low molecular weight substances, such as monomers, oligomers, plasticizers or catalyst components might migrate from the packaging into the pharmaceutical and pose a safety risk to patients this way. These considerations are especially problematic for pharmaceutical liquids due to the direct contact of the packaging with the product and the likelihood that soluble substances derived from the packaging are rapidly diffusing into the solution.
Common leachables in plastic material are phthalates or phthalate esters, which are esters of phthalic acid and mainly used as plasticizers to soften polyvinyl chloride (PVC). In studies of rodents exposed to certain phthalates, high doses have been shown to change hormone levels and cause birth defects. Examples of phthalates are diethylphthalate (DEP), di-iso-butylphthalate, di-butylphthalate (DBP) and dicyclohexylphthalate (DCHP).
Oleamide and erucamide fatty acid derivatives are the most common slip agents used in polyethylene film. Other slip agents are decanamide, dodecanamide, hexadecanamide, stearamide.
2-t-butyl-, 4-t-butyl and 2,4-Di-t-butyl phenol are monomers of tertiary butyl phenol formaldehyde resins and may cause allergic reactions.
Divinylbenzene (DVB) is a mixture of 1,3- and 1,4-Divinylbenzene. Divenylbenzene is used as a cross-linker in styrene polymers. It is known to be a strong irritant and slightly genotoxic.
Since the end of 2005, the European Medicines Agency (EMEA) has consequently required the exact identification and quantification of migrating substances to comply with the Guideline on Plastic Immediate Packaging Materials (CPMP/QWP/4359/03). This guideline demands a toxicological assessment of all migrating substances regardless of their amount. Because it seems reasonable to assume that below a certain level a substance is of no risk to human safety, the product quality research institute (PQRI, Arlington, Va., USA) proposed a safety concern threshold (SCT) in response to this guideline. A SCT value of 150 ng/day was recommended basing on a scientific rationale for orally inhaled and nasal drug products (OINDP) as a threshold below which no toxicological qualification for a leachable is necessary. The parenteral and ophthalmic drug products (PODP) leachables and extractables working group of the PQRI advised to adopt this value for pharmaceutical solutions, which includes dialysis solutions used for peritoneal dialysis (PD) and hemodialysis (HD) as well. PD and HD are treatment modalities for patients with an acute or chronic renal failure.
Solutions used for the peritoneal dialysis place the highest demands on the quantification of leachables. Usually a volume of 2 liter dialysis solution is introduced in the abdomen of the patient. It remains there for about 5 hours and is finally replaced with fresh solution. This results in a total volume of about 10 liters per day. The total volume doubles if automated solution changers are used. Therefore the determination of the SCT of 150 ng/day requires an analytical method with a limit of detection (LOD) of 15 ng/L (10 L dialysis solution per day) or even 7.5 ng/L (20 L per day). For hemodialysis solutions, or hemofiltration solutions to be more precisely, a LOD of 35 ng/L is required. This value was calculated by assuming three hemofiltration treatments per week with a 4 hour duration and a final exchanged volume of 10 L per treatment.
Analytical methods for the determination of leachables in pharmaceutical solutions below the SCT have to fulfill at least two requirements. Firstly they must be able to quantify a possibly large number of compounds in a mixture simultaneously and secondly they have to be sensitive enough for trace analysis in regard to their limit of detection (LOD) and limit of quantification (LOQ), respectively.
A very common technique used for this purpose is liquid-liquid extraction (LLE) followed by a gas chromatographic (GC) separation of the extracted sample. The extraction of the aqueous sample with an organic solvent is necessary especially for the enrichment of leachables and to allow the injection into the GC column. Typically, 100 g of an aqueous sample is mixed with 4 g of chloroform for 1 h. The main disadvantages of LLE are its time-consumption, the high costs and the usage of large volumes of potentially toxic solvents, which are hazardous to health as well as to environment. The limit of quantification of LLE depends on the specific compound and is between 10 μg/kg and 250 μg/kg, which is not sufficient to meet the requirements of SOT.
WO 91/15745 discloses the method of solid-phase microextraction (SPME) which offers an improved limit of quantification. This method uses fibers coated with polydimethyl-siloxane (PDMS), which are placed in a needle of a syringe-like arrangement to extract and enrich non-polar compounds from an aqueous sample. The fiber has only a very limited absorption capacity for substances which are to be examined and, moreover, is only dipped into the stirred carrier fluid, so that consequently the sensitivity of the analysis itself leaves something to be desired if the coated fiber is vibrated.
EP 1 039 288 discloses a modified SPME setup. This method uses a PDMS coated stir bar and is, therefore, called stir bar sorptive extraction (SBSE).
There is still a demand for an analytical method to determine leachables and pollutants in medical solutions like, e. g., dialysis solutions, which meets the requirements of SOT.